Université Pierre et Marie Curie - Paris 6, Paris, France.
Psychopharmacology (Berl). 2010 May;209(4):313-8. doi: 10.1007/s00213-010-1797-8. Epub 2010 Mar 23.
Ketamine, a non-competitive N-methyl-D: -aspartic acid antagonist, has been widely used for anaesthetic purposes. At sub-anaesthetic dosage, it induces a dissociative state similar to schizophrenia. The discovery of this effect on dissociative state has led to its use as a pharmacological model of schizophrenia and has also been responsible for its illegal use as a recreational drug. Whereas the former has provided invaluable information, the latter has demonstrated that repeated administration of ketamine induces tolerance. Surprisingly, a review of the relevant literature shows that tolerance to sub-anaesthetic doses of ketamine is largely unreported in neuropharmacological studies.
In order to investigate this caveat, we have performed a post hoc analysis of the behavioural effects induced by repeated injections of sub-anaesthetic doses of ketamine observed in five consecutive monkeys performing two oculomotor tasks. Ketamine effects were quantified by the animals' performances and latencies in a prosaccade and an antisaccade task, two oculomotor paradigms that are impaired after ketamine administration.
Although the result of the initial injections confirmed a clear behavioural effect of ketamine injections in all monkeys, subsequent administrations showed that a tolerance eventually appeared in all monkeys. The profile of this tolerance exhibited however a large inter-subject variability.
Psychopharmacological experiments using ketamine as a pharmacological model of psychosis should therefore consider the kinetic and time course of these effects in each individuals and take them into account in the design of experimental protocols.
氯胺酮是一种非竞争性 N-甲基-D-天冬氨酸拮抗剂，被广泛用于麻醉目的。在亚麻醉剂量下，它会引起类似于精神分裂症的分离状态。这种对分离状态的发现导致了它被用作精神分裂症的药理学模型，也导致了它被非法用作娱乐药物。虽然前者提供了宝贵的信息，但后者表明，重复给予氯胺酮会导致耐受。令人惊讶的是，对相关文献的回顾表明，在神经药理学研究中，氯胺酮亚麻醉剂量的耐受现象在很大程度上没有被报道。
为了研究这一注意事项，我们对连续五只猴子在执行两个眼球运动任务时重复给予亚麻醉剂量氯胺酮所引起的行为效应进行了事后分析。氯胺酮的作用通过动物在快速眼动和反向眼动任务中的表现和潜伏期来量化，这两个眼球运动范式在氯胺酮给药后会受到损害。
尽管最初的注射结果证实了所有猴子中氯胺酮注射的明显行为效应，但随后的给药表明，所有猴子最终都出现了耐受。然而，这种耐受的模式表现出很大的个体间变异性。
因此，使用氯胺酮作为精神分裂症药理学模型的精神药理学实验应考虑这些效应在每个人中的动力学和时间过程，并在实验方案的设计中考虑到它们。
